Detailed Description of the Invention
[0001] This invention relates to novel dibenz [b,e] oxepin derivatives, the pharmaceutically
acceptable acid addition salts thereof and a pharmaceutical composition containing,
as the active ingredient, a dibenz [b,e] oxepin derivative.
[0002] More particularly, the present invention pertains to a novel dibenz [b,e] oxepin
derivative represented by the following general formula (Ia):
wherein R
11 represents an alkyl group containing 1 to 5 carbon atoms, an alkoxy group containing
1 to 5 carbon atoms, a halogen atom, a cyclohexyl group or a phenyl group; and R
21 represents (1)
wherein X represents a hydrogen atom, a hydroxy group, an amino group or a substituted
aralkyl group containing 7 to 20 carbon atoms, and n represents 0 or an integer of
1 to 3
wherein Y represents an alkylamino group containing 1 to 5 carbon atoms, an aralkyl
group containing 7 to 20 carbon atoms, a substituted aralkyl group, an aralkyloxy
group containing 7 to 20 carbon atoms, an aralkylamino group containing 7 to 20 carbon
atoms, a heterocyclic ring or a substituted heterocyclic ring, and n has the same
meaning as defined before; provided tnat wnen R
11 represents an alkyl group, an alkoxy group or a halogen atom, X does not represent
a hydrogen atom; and the pharmaceutically acceptable acid addition salts thereof.
[0003] In addition, the present invention pertains to a pharmaceutical composition comprising
a pharmaceutical carrier and, as an active ingredient, an effective amount of a dibenz
[b,e] oxepin derivative represented by the following general formula (I)
wherein R
1 represents an alkyl group containing 1 to 5 carbon atoms, an alkoxy group containing
1 to 5 carbon atoms, a halogen atom, a cyclohexyl group or a phenyl group; and R
2 represents (1)-N-N-(CH
2)
n-X wherein X represents a hydrogen atom, a hydroxy group, an amino group or a substituted
aralkyl group containing 7 to 20 carbon atoms, and n has the same meaning as defined
before (2)
-NH-(CH
2)
n- Y, wherein Y and n have the same meaning as defined above; and the pharmaceutically
acceptable acid addition salts thereof.
[0004] Compound I, represented by the general formula (I) has antichlolinergic, antihistaminergic,
antiasthmatic and antiplatelet aggregation activities, and is therefore useful as
a sposmolysant, an antihistaminic, an antiasthmatic agent and as a medicament for
cardiovascular or cerebrovascular diseases, respectively.
[0005] U.S. Patent No. 3,509,176 discloses
dibenzo-oxepine derivatives which exhibit muscle-relaxing, transquilizing and anti-convulsant
activities. Although not specifically disclosed, compounds 66 to 70 of the present
invention are within the scope of the general formula set forth therein.
[0006] The present invention is described in detail below.
[0007] In compound I and compound Ia, represented by the general formulae (I) and (Ia),
respectively, the alkyl group containing 1 to 5 carbon atoms, and represented by R
and R
11, includes a methyl group, an ethyl group, a propyl group, a butyl group, an amyl
group, etc.
[0008] The alkoxy group containing 1 to 5 carbon atoms includes a methoxy group, an ethoxy
group, a propoxy group, a butoxy group, a pentoxy group, etc.
[0009] The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, an iodine
atom,
[0010] The aralkyl group, containing 7 to 20 carbon atoms represented by Y, and the aralkyl
group of the substituted aralkyl group containing 7 to 20 carbon atoms, represented
by X, includes a benzyl group, a phenylethyl group, a phenylpropyl group, a phenylbutyl
group, a diphenylmethyl group, etc. Typical substituted aralkyl groups containing
7 to 20 carbon atoms, and represented by X, include a bis(fluoro-phenyl)methyl group,
etc.
[0011] The alkylamino group containing 1 to 5 carbon atoms, and represented by Y, includes
a methylamino group, an ethylamino group, a propylamino group, a dimethylamino group,
a diethylamino group, etc.
[0012] The substituent of the aralkyl groups includes halogen atoms such as fluorine and
chlorine, alkoxy groups such as methoxy and ethoxy, etc.
[0013] The aralkyloxy group containing 7 to 20 carbon atoms includes a benzyloxy group,
a diphenylmethoxy group, etc.
[0014] The aralkylamino group containing 7 to 20 carbon atoms includes a benzylamino group,
a dibenzylamino group, etc.
[0015] The heterocyclic ring includes piperazine, piperidine, morpholine, pyrrolidine, pyridine,
quinuclidine, benzodioxane, indole, auinoline, etc.
[0016] The substituent of the heterocyclic ring includes an alkyl group such as a methyl
group, an ethyl group and a propyl group,
etc.
[0017] The acid addition salts of compound I include inorganic acid addition salts such
as hydrochloride, sulfate, hydrobromide, phosphate, etc. and organic acid addition
salts such as acetate, maleate, fumarate, tartrate, citrate, oxalate, benzoate, etc.
[0018] The present compound can be prepared according to the following processes well known
in the field of organic synthesis chemistry using known compound II represented by
the following general formula (II):
(wherein R
1 has the same meaning as defined above) as intermediates.
[0019] Processes for preparing known compound II are described in J. Med. Pharm. Chem.,
5, 1207 (1962); Monatsh. Chem., 93, 889 (1962); Angew. Chem., 74, 31 (1962); Belgian
Patent 623,259, etc.
[0020] For example, the known compound II may be prepared according to the following reaction
scheme:
[0021] A typical process for preparing the compounds of the present -invention is Process
A described below.
In the above formulae, R
1 and R
2 have the same meaning as defined above, and Z represents a halogen atom.
[0022] Compound II is reduced to compound III, and the. resulting compound III is then reacted
with a halogenating agent to form compound IV. The compound IV is subsequently reacted
with an amine such as . X-(CH
2)
n-N-NH (compound V), Y-(CH
2)
n-NH
2. (compound VI) (wherein X, Y and n have the same meaning as defined before) or
(compound VII) to obtain compound I.
[0023] Process A is described in more detail below.
[0024] Compound III can be usually obtained by reducing compound II using a metal hydride
such as lithium aluminum hydride and sodium borohydride . or through catalytic .hydrogenation.
[0025] In the case of reducing compound II using lithium aluminum hydride, compound II is
first dissolved in an anhydrous solvent such as diethyl ether, diisopropyl ether,
tetrahydrofuran, diethylene glycol dimethyl ether, or the like, then 0.3 to 2.0 equivalents
based on said compound II, of lithium aluminum hydride is added thereto, followed
by stirring for 30 minutes to 3 hours at a temperature of from 0°C to the boiling
point of the solvent to complete the reduction. Then, the reaction mixture is post-treated
in a conventional manner to obtain compound III.
[0026] In the case of reducing compound II using sodium borohydride, compound II is dissolved
in a solvent such as water, methanol, ethanol, isopropanol, diethylene glycol dimethyl
ether, dimethylformamide, dimethylsulfoxide, or the like, then 0.3 to 1.0 equivalent
based on said compound II, of sodium borohydride is added thereto, followed by stirring
for one to 8 hours at a temperature of from O to 40°C to complete the reduction. Then,
the reaction mixture is post-treated in a conventional manner to obtain compound III.
[0027] On the other hand, in the case of reducing compound II according to a catalytic hydrogenation
process, compound II is hydrogenated for 2 to 7 hours in a solvent such as methanol,
ethanol, dioxane or the like at ordinary tempertures and at atmospheric pressure using
a catalyst such as platinum oxide, palladium carbon, Raney nickel, or the like, to
obtain compound III. In this procedure the reaction should not be carried out at high
temperatures, because it can simultaneously cause hydrogenolysis.
[0028] The thus obtained compound III is then converted to compound IV using various halogenating
agents. This halogenation can easily be conducted using hydrogen halide, phosphorus
halide or thionyl halide as a halogenating agent. Suitable hydrogen halides include
concentrated hydrochloric acid, concentrated hydrobromic acid, hydrogen bromide gas,
etc. Compound IV can be obtained by reacting compound III with these hydrogen halides
per se, or if necessary, in the presence of concentrated sulfuric acid, zinc chloride,
pyridine, triethylamine or the like at a temperature of 0 to 60°C for 30 minutes to
3 hours. Suitable phosphorus halides include phosphorus trichloride, phosphorus pentachloride,
phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, phosphorus
oxybromide, etc. These phosphorus halides are reacted per se in an excess amount with
compound III, or in a solvent such as benzene, toluene, xylene, dichloromethane, chloroform,
carbon tetrachloride, dimethylformamide, diethyl ether, or the like, at a temperature
of 0 to 70°C for one to 5 hours, if necessary in. the presence of a tertiary amine
such as pyridine, quinoline, dimethylaniline or triethylamine to obtain compound IV.
Suitable thionyl halides include thionyl chloride, thionyl bromide, etc. Compound
IV can be obtained according to the same procedure as that using the aforesaid phosphorus
halides.
[0029] The thus obtained compound I
V is then reacted with compound V, VI or VII to obtain compound I. Namely, compound
I is prepared by reacting compound IV with 2 to 10 equivalents of compound V, VI or
VII, if necessary in an inert solvent such as dichloromethane, chloroform, tetr chloromethane,
benzene, toluene, xylene, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
n-hexane, cyclohexane, acetonitrile, carbon disulfide, ethyl acetate, dimethylformamide
or the like, at a temperature of -10 to 120°C for 30 minutes to 3 hours. One equivalent
of compound V, VI or VII is enough to complete the reaction if a base such as sodium
carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate,
pyridine, quinoline, dimethylaniline or triethylamine is added to the reaction solution
in order to bind hydrogen halide as a by-product. The desired compound is obtained
as a free base in a crystalline or oily form. If necessary, the desired compound can
be further purified through column chromatography or recrystallization.
[0030] Acid addition salts of the desired componds can be easily prepared by reacting the
desired componds with usable inorganic acids such as hydrochloric acid, sulfuric acid,
hydrobromic acid and phosphoric acid or organic acids such as acetic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, oxalic acid and benzoic acid in a
conventional manner.
[0031] Furthermore, the present compounds can be also prepared according to the following
processes B to E.
[0032] In the above formulae, R
1 and R
2 have the same meaning as defined above, and R
3 represents an alkyl group, a phenyl group or a substituted phenyl group.
[0033] The substituted phenyl group includes p-tolyl group, etc.
[0034] Compound I can be obtained by reacting compound III obtained by process A with a
sulfonylating agent to prepare compound VIII, and then reacting compound VIII with
an amine (compound V, VI or VII).
[0035] In the above formulae, R
1, Y, and n have the same meaning as defined above.
[0036] Compound I' can be obtained by reducing compound IX prepared by dehydration condensation
between compound II and compound VI.
[0037] In the above formulae, R
1, Y, and n have the same meaning as defined above, and W represents a halogen atom
or a sulfonyloxy group.
[0038] The halogen atom includes a chlorine atom, bromine atom, iodine atom.
[0039] The sulfonyloxy group includes a methylsulfonyloxy group, phenylsulfonyloxy group,
p-toluenesulfonyloxy group, etc.
[0040] In the above formulae, R
1 and Y have the same meaning as defined above, and n represents an integer of 1 to
3. Compound I' can be obtained by reducing compound XIII prepared by dehydration condensation
between compound X and compound XII.
[0042] The structural formulae of the above-illustrated compounds are shown by defining
R
2, R
1 and the position of R
1 according to the general formula (I) below:
[0043] The pharmacological activity of the compound I represented by the general formula
(I) is illustrated in (a) an acute toxicity test, (b) a test for anticholinergic effects
on the isolated ileum of a guinea-pig, (C) a test for antihistaminergic effects on
the isolated ileum of a guinea-pig, and (d) a test for the inhibition of platelet
aggregation. Each of these tests is described in detail below.
(a) Acute toxicity test
[0044] Groups of male dd-strain rats (each group consisting of five rats) weighing 20 +
1 g were used. The compounds of the present invention were administered orally (po:
0.3 mg/g) or intraperitoneally (ip: 0.1 mg/g). The MLD (minimum lethal dose) was calculated
from the mortality for 7 days after the administration to obtain the results given
in Table 1.
(b) Test for anticholinergic effects on the isolated ileum of guinea-pig (In vitro
test)
[0045] Male Hartly-strain guinea-pigs weighing about 250 g are killed and the abdomen is
opened. The part (2-3 cm in length) of the ileum 10 cm away from the caecum to the
pylorus is cut off as a preparation. The preparation is suspended with serre-fine
in a Magnus bath containing 10 ml of Tyrode's solution at 32 ± 1°C under an air bubble.
The contraction of the ileum is recorded on Kymograph through hebel when 0.1 ml of
acetylcholine at a concentration.of 10
-3 g/ml is added to the Tyrode's solution.
[0046] On the other hand, 3 minutes after administration of the test compounds, the same
procedure as mentioned above is carried out to record the contraction. The test compounds
showing a depressing ratio of 80% or more, compared with the concentration of the
ileum by acetylcholine alone, are concluded to have anticholingenergic activity. A
final concentration of the test compounds is reduced until the depressing ratio is
less than 80% to obtain the minimum effective dose (hereinafter referred to as MED).
The results are shown in Table 1.
(c) Test for antihistaminergic effects on the isolated ileum of guinea-pig (In vitro
test)
[0047] In this test, 0.1 ml of histamine at a concentration of 5 x 10
-3 g/L is used. The MED exhibiting antihistaminergic activity is obtained by a procedure
similar to that used to determine the anticholinergic effect as described above. The
results are shown in Table 1.
(d) Test for the inhibition of platelet aggregation
[0049] As is apparent from Table 1, the present compounds have anticholinergic, antihistaminergic,
antiasthmatic and antiplatelet aggregation activities. The compounds as such are useful'
as a sposmolysant, an antihistaminic, an antiasthmatic agent and as a medicament for
cardiovascular or cerebrovascular diseases.
[0050] In view of the exhibited pharmacological activity, a compound represented by the
general formula (I) may be used in various pharmaceutical forms for administration.'
Pharmaceutical compositions of the present invention are prepared by uniformly mixing
an effective amount of the compound as the active ingredient, in free form or as an
acid addition, salt, with a pharmaceutically acceptable carrier. The carrier may take
various forms depending on the pharmaceutical form . suitable for administration.
It is preferable that the pharmaceutical composition is in single administration form
suitable for administration orally or by injection.
[0051] To prepare the compositions of the present invention for oral administration, any
useful pharmaceutical carrier may be used. For example, oral liquid preparations such
as suspensions and syrups can be prepared using water, sugar (e.g. sucrose, sorbitol
and fructose), glycols (e.g. polyethyleneglycol and propyleneglycol), oils (e.g. sesame
oil, olive oil and soybean oil), antisepics (e.g. alkyl parahydroxybenzoate and dehydroacetic
acid), flavours (e.g. strawberry flavour and peppermint) and the like. Powders, pills,
capsules and tablets can be prepared using excipients (e.g. lactose, glucose, sucrose
and mannitol), disintegrators (e.g. starch, sodium alginate and carboxymethyl cellulose
calcium), lubricants (e.g. magnesium stearate and talc), binders (e.g. polyvinyl alcohol,
hydroxypropylcellulose, and gelatin), surfactants (e.g. sucrose fatty acid ester and
sorbitan fatty acid ester), plasticizers (e.g. glycerin) and the like.
[0052] Tablets and capsules are the most useful single oral administration forms because
of the ease of administration. To make tablets and capsules solid pharmaceutical carriers
are used.
[0053] Where pharmaceutical compositions for parenteral administration are desired, the
carrier for the most part consists of sterile aqueous solutions. The carrier, however,
may also contain other components to help the dissolution of the dibenz [b,e] oxepin
derivatives.
[0054] For example, an injection solution can be prepared using a carrier consisting of
a mixture of salt solution and glucose solution or saline solution and glucose solution.
[0055] The suspensions for injection can be prepared using an appropriate liquid carrier,
dispensing agent and the like. Although the amount of the active ingredient can be
varied over a rather wide range, 1 - 20 mg/kg/day in one dose or several divided doses
is generally considered to be effective.
[0056] Certain specific embodiments of the invention are illustrated by the following representative
examples.
Example 1
[0057] Preparation of compound 1: .
2-ethyl-11-[2-(diethylamino)ethyl]amino-6,11-dihydrodibenz [b,e]oxepin
[0058] In this example, 4.8 g of
2-ethyl-6,11-dihydrodibenz [b,e]oxepinone-11 is dissolved in 30 ml of ethanol, and
0.4 g of sodium borohydride is added thereto, followed by stirring at room temperature
for 5 hours. The reaction solution is concentrated under reduced pressure to distill
off ethanol. Then, 20 ml of water and 20 ml of chloroform are added to the residue
and after shaking, an aqueous layer is discarded. A chloroform layer is dehydrated
and concentrated under reduced pressure to obtain 4.8 g of crude crystals of 2-ethyl-11-hydroxy-6,11-dihydrodibenz[b,e]oxepin.
Recrystallizatin of the crude crystals from 50 ml of n-hexane gives 4.6 g of pure
crystals in a yield of 96%. The resulting crystals are dissolved in 20 ml of . dichloromethane,
and 4.6 g of thionyl chloride is dropwise added thereto for 15 minutes. After completion
of the dropwise addition, the resulting.mixture is stirred for 30 minutes at room
temperature. The reaction solution is concentrated under reduced pressure to distill
off dichloromethane and excess thionyl chloride. Thus, 5.0 g of crude crystals of
2-ethyl-11-chloro-6,11-dihydrodibenz[b,e]oxepin are obtained as a concentrated residue.
[0059] The crude-product is dissolved in 10 ml of toluene and added dropwise to a solution
of 4.0 g of N,N-diethylethylenediamine in 20 ml of toluene, followed by stirring for
3 hours at room temperature. After completion of the reaction, 20 ml of water is added
thereto, and the pH of the solution is adjusted to 2.0 with concentrated hydrochloric
acid. A toluene layer was discarded, and 20 ml of ethyl ether is added to an aqueous
layer, followed by readjusting the pH of the solution to 10.5 with a 10 N sodium hydroxide
aqueous solution. An aqueous layer is discarded, and an ethyl ether layer is dehydrated
and concentrated under reduced pressure..The residue is purified through'silica gel
chromatography. Concentration of the main fractions gives 4.9 g of 2-ethyl- 'll-[2-(diethylamino)ethyl]
amino-6,11-dihydrodibenz [b,e] oxepin [compound 1] in an oily free base in a yield
of 76
%. This product is dissolved in 150 ml of ethyl ether, and a hydrogen chloride gas
is blown thereinto to obtain 5.1 g of dihydrochloride crystals.
[0060] m.p.: (the dihydrochloride is too hygroscopic to measure)
[0061] IR absorption spectrum.(NaCl cell, cm
-1):
2970, 1500, 1230, 1125, 1015, 825
[0062] NMR spectrum (CDCl
3, δ value, ppm):
0.94(t, 6H), 1.18(t, 3H), 2.03-3.07(m, 11H), 4.52(s, 1H), 4.81 (d, 1H), 6.17(d, 1H),
6.60-7.57 (m, 7H)
[0063] Elemental analysis of dihydrochloride:
Examples 2 to 36
Compound 2: 2-ethyl-11-{3-(diethylamino)propyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0065] m.p.: (dihydrochloride being too hygroscopic to measure)
[0066] IR absorption spectrum (NaCl cell, cm
-1):
2970, 1500, 1380, 1230, 1020, 830
[0067] NMR spectrum (CDCl
3, δ value, ppm):
0.94(t, 6H), 1.19(t, 3H), 0.71-1.88 (m, 2H), 2.14-2.88(m, 11H), 4.50(s, 1H), 4.78(d,
1H), 6.21 (d, 1H), 6.68-7.48 (m, 7H)
[0068] Elemental analysis of dihydrochloride:
Compound 3: 2-fluoro-11-{3-(diethylamino)propyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0069] m.p.: (dihydrochloride being too hygroscopic to measure)
[0070] IR absorption spectrum (NaCl cell, cm
-1):
2970, 1495, 1380, 1260, 1010, 815
[0071] NMR spectrum (CDCl
3, δ value, ppm):
0.93(t, 6H), 1.19-1.93 (m, 2H), 2.14 (s, 1H), 1.93-2.94(m, 8H), 4.49(s, 1H), 4.82(d,
1H), 6.10(d, 1H), 6.53-7.46 (m, 7H)
[0072] Elemental analysis of dihydrochloride:
Compound 4: 2-methyl-11-{3-(diethylamino)propyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0073] m.p.: (dihydrochloride being too hygroscopic to measure)
[0074] IR absortion spectrum (NaCl cell, cm
-1):
2970, 1500, 1225, 1125, 1015, 820
[0075] NMR spectrum (CDCl
3, δ value, ppm):
0.93(t, 6H), 1.22-1.83 (m, 2H), 2.23(s, 3H), 1.88-2.85(m, 9H), 4.48(s, 1H), 4.79(d,
1H), 6.22(d, 1H), 6.52-7.45 (m, 7H)
[0076] Elemental analysis of dihydrochloride:
Compound 5: 2-chloro-11-{3-{diethylamino)propyl}amino-6,11-dihydrodibenz [b,e]oxepin
[0077] m.p.: (dihydrochloride being too hygroscopic to measure)
[0078] IR absorption spectrum: (NaCl cell, cm
-1) 2970, 1480, 1255, 1115, 1005, 820
[0079] NMR spectrum (CDCl
3, δ value, ppm):
0.34 (t, 6H), 1.25-1.83 (m, 2H), 2.04(s, 1H), 1.95-2.95(m, 8H), 4.51(s, 1H), 4.81(d,
1H), 6.34 (d, 1H), 6.61-7.55 (m, 7H)
[0080] Elemental analysis of dihydrochloride:
Compound 6: 4-methyl-11-{3-{diethylamino)propyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0081] m.p.: (dihydrochloride being too hygroscopic to measure)
[0082] IR absorption spectrum (NaCl cell, cm
-1):
2970, 1475, 1330, 1205, 1090, 1015
[0083] NMR spectrum (CDCl
3, δ value, ppm):
0.92 (t, 6H), 1.22-1.89 (m, 2H), 2.21(s, 3H), 1.89-2.79 (m, 9H), 4.50 (s, 1H), 4.83(d,
1H), 6.10(d, 1H), 6.52-7.42(m, 7H)
[0084] Elemental analysis of dihydrochloride:
Compound 7: 2-methoxy-11-{3-(diethylamino)propyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0085] m.p.: (dihydrochloride being too hygroscopic to measure)
[0086] IR absorption spectrum (NaCl cell, cm
-1):
2970, 1500, 1380, 1260, 1045, 815
[0087] NMR spectrum (CCl
4, δ value, ppm):
0.89 (t, 6H), 1.16-1.79 (m, 2H), 1.95(s, 1H). 1.79-2.96 (m, 8H), 2.63 (s, 3H), 4.39(s,
1H), 4.71(d, 1H), 6.03(d, 1H), 6.33-7.36 (m, 7H)
[0088] Elemental analysis of dihydrochloride:
Compound 8: 2-methyl-11-{2-(diethylanino)ethyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0089] m.p.: (dihydrochloride being too hygroscopic to measure)
[0090] IR absorption spectrum (NaCl cell, cm
-1):
2960, 1500, 1260, 1230, 1010, 815
[0091] NMR spectrum (CDCl
3, δ value, ppm):
0.94 (t, 6H), 2.23(s, 3H), 2.12-2.85 (m, 9H), 4.50 (s, 1H), 4.79 (d, 1H), 6.19 (d,
1H), 6.55-7.35 (m, 7H)
[0092] Elemental analysis of dihydrochloride:
Compound 9: 2-fluoro-11-{2- (diethylamino) ethyl} amino- 6,11-dihydrodibenz[b,e]oxepin
[0093] m.p.: (dihydrochloride being too hygroscopic to measure)
[0094] IR absorption spectrum (NaCl cell, cm
-1):
2970, 1495, 1380, 1260,'1015, 815
[0095] NMR spectrum (CDCl
3, δ value, ppm):
0.94(t, 6H), 1.76-2.82(m, 9H), 4.53(s, 1H), 4.84(d, 1H), 6.10(d, 1H), 6.46-7.39 (m,
7H)
[0096] Elemental analysis of dihydrochloride:
Compound 10: 2-chloro-11-{2-(diethylamino)ethyl}amino-6 ,11-dihydrodibenz [b, e] oxepin
[0097] m.p.: (dihydrochloride being too hygroscopic to measure)
[0098] IR absorption spectrum (NaCl cell, cm
-1):
2970, 1480, 1260, 1120, 1010, 820
[0099] NMR spectrum (CDCl
3 , δ value, ppm):
6H), 1.80 -2.80 (m, 9H),4.49 (s, 1H), 0.93(t, 6H), 1.80- 2.80(m, 9H), 4.49(s, 1H),
4.78(d, 1H), 6.30(d, 1H), 6.60-7.43 (m, 7H)
[0100] Elemental analysis of tartrate:
Compound 11: 2-(1-methyl propyl-11-{2-(diethylamino)-ethyl amino-6,11-dihydrodibenz[b,e]oxepin
[0101] m.p.: (dihydrochloride being too hygroscopic to measure)
[0102] IR absorption spectrum (NaCl cell, cm
-1):
2960, 1500, 1230, 1120, 1010, 825
[0103] NMR spectrum (CCl
4 , δ value, ppm):
0. 81 (t, 3H), 0.94(t, 6H), 1.18(d, 3H), 1.00 - 1.85 (m, 2H), 1.98-2.85(m, 10H), 4.41(s,
1H), 4.66 (d, 1H) , 6.31 (d, 1Fi) , 6.51 - 7.31 (1, 7H)
[0104] Elemental analysis of dinwdrochlorice:
Compound 12: 4-methyl-11-{2-(diethylamino)ethyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0105] m.p.: (dihydrochloride being too hygroscopic to measure)
[0106] IR absorption spectrum (NaCl cell, cm
-1) :
2970, 1470, 1375, 1200; 1085, 1010
[0107] NMR spectrum (CDCl
3, δ value, ppm):
0.92(t, 6H), 2.20(s, 3 H), 1. 63 - 3. 03 (m, 9H), 4. 52 (s, 1H), 4. 85 (d,. 1H) ,
6. 07 (d, 1H), 6. 50 - 7. 50 (m, 7H)
[0108] Elemental analysis of dihydrochloride:
ompound 13: 2-methoxy-11-{2-(diethylamino)ethyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0109] m.p.: (dihydrochloride being too hygroscopic to measure)
[0110] - IR absorption spectrum (NaCl cell, cm
-1) :
2970, 1500, 1380; 1260, 1045, 815
[0111] NMR spectrum (CDCl
3, δ value, ppm):
0.93(t, 6H), 1.74-2.84(m, 9H), 3.69(s, 3H), 4.50(s, 1H), 4.84(d, 1H), 5.96(d, 1H),
6.50-7.40 (m, 7H)
[0112] Elemental analysis of dihydrochloride:
Compound 14: 2-methyl-11-{3-(dimethylamino)propyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0113] m.p.: (dihydrochloride) 187°C (d.)
[0114] IR absorption spectrum (NaCl cell, cm
-1):
2940, 1500, 1460, 1260,.1015, 820
[0115] NMR spectrum (CDCl
3, δ value, ppm):
2.15 (s, 6H), 2.25(s, 3H), 1.17-2.80(m, 7H), 4.51(s, 1H), 4.83(d, 1H), 6.19(d, 1H),
6.67-7.37 (m, 7H)
[0116] Elemental analysis of dihydrochloride:
Compound 15: 2-ethyl-11-{3-(dimethylamino)propyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0117] m.p.: (dihydrochloride being too hygroscopic to measure)
[0118] IR absorption spectrum (NaCl cell, cm
-1):
2930, 1500, 1230, 1125, 1010, 830
[0119] NMR spectrum (CDCl
3, δ value, ppm):
1.19 (t, 3H), 1.40-1.90 (m, 2H), 2.13(s, 6H), 1.97-2.90(m, 7H), 4.50(s, 1H), 4.79(d,
1H) , 6.19(d, 1H), 6.67-7.47 (m, 7H)
[0120] Elemental analysis of dihydrochloride:
Compound 16: 2-methyl-11-{2-(dimethylamino)ethyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0121] m.p.: (dihydrochloride) 144-147°C
[0122] IR absorption spectrum (NaCl cell, cm
-1) :
2940, 1500, 1265, 1125, 1015, 820
[0123] NMR spectrum (CDCl
3, δ value, ppm):
210 (s, 6H), 2.22 (s, 3H) , 1.90-2.87(m, 5H), 4.48(s, 1H), 4.79(d, 1H) , 6.19 (d,
1H) , 6.83-7.44 (m, 7H) Elemental analysis of dihydrochloride:
Compound 17: 2-ethyl-11-(2-(dimethylamino)ethyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0124] m.p.: (dihydrochloride being too hygroscopic to measure)
[0125] IR absorption spectrum (NaCl cell, cm
-1) :
2960, 1500,1230, 1125,1015, 825
[0126] NMR spectrum (CCl
4, δ value, ppm):
1.18(t, 3H), 2.08(s, 6H), 1.89-2.82(m, 7H), 4.40(s, 1H), 4.65(d, 1H), 6.29 (d, 1H),
6.49-7.36 (m, 7H)
[0127] Elemental analysis of dihydrochloride:
Compound 18: 2-fluoro-11-{2-(dimethylamino)ethyl)amino-6,11-dihydrodibenz [b,e]oxepin
6,11-dihydrodibenz[b,e]oxepin
[0128] m.p.: (dihydrochloride) 192°C (d.)
[0129] IR absorption spectrum (Nacl cell, cm
-1) :
2940, 1495, 1260, 1140, 1010, 815 :
[0130] NMR spectrum (CDCl
3, δ value, ppm) :
2. 09 (s, 6H), 1.86-2.86(m, 5H), 4.48(s, 1H) 4.80(d, 1H), 6.07(d, 1H), 6.49-7.39 (m,
7H)
[0131] Elemental analysis of dihydrochloride:
Compound 19: 2-chloro-11-{2-(dimethylamino)ethyl)amino-6,11-dihydrodibenz [b, e]oxepin
[0132] m.p.: (tartrate) 85-88°C
[0133] IR absorption spectrum (NaCl cell, cm
-1):
2320, 1480, 1255, 1115, 1005, 820
NMR spectrum (CDCl3, δ value, ppm):
2.05 (s, 6H), 1.82-2.82(m, 5H), 4.47(s, 1H), 4.77(d, 1H),.6.30(d, 1H),. 6.56-7.42
(m, 7H)
Elemental analysis of tartrate:
Compound 20: 2-methyl-11-(3-quinuclidinyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0134] m.p.: (dihydrochloride) 165°C (d.)
[0135] IR absorption spectrum (NaCl cell, cm
-1) :
2970, 1500, 1380, 1230, 1050, 820
[0136] NMR spectrum (CDCl
3, δ value, ppm):
2.24(s, 3H), 0.84-3.14(m, 13H), 4.52(s, 1H), 4.78 & 4.79(twin d, 1H), 6.13 & 6.25
(twin d, 1H) 6.51-7.37 (m, 7H)
[0137] Elemental analysis of dihydrochloride:
Compound 21: 2-ethyl-11-(3-quinuclidinyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0138] m.p. : (dihydrochloride) 149°
C (d.)
[0139] IR absorption spectrum (NaCl cell, cm
-1):
2930, 1500, 1320, 1230, 1120, 1015
[0140] NMR spectrum (CCl
4+ CDCl
3, δ value, ppm):
1.19 (t, 3H), 0.74-3.18(m, 15H), 4.53(s, 1H), 4.78(d, 1H), 6.16 & 6.27 (twin d, 1H),
6.48-7.41 (m, 7H)
[0141] Elemental analysis of dihydrochloride:
Compound 22: 2-fluoro-11-(3-quninuclidinyl)amino-6,11-dihydrodibenz [b, e]oxepin
[0142] m.p.: (dihydrochloride) 188°C (d.)
[0143] IR absorption spectrum (NaCl cell, cm
-1) :
2930, 1500, 1260, 1140, 1015, 820
[0144] NMR spectrum (CCl
4 + d
6-DMSO, δ value, ppm):
0.62-2.09(m, 13H), 4.55(s, 1H), 4.79(d, 1H) 6.04 & 6.14 (twin d, 1H), 6.39-7.42 (m,
7H)
[0145] Elemental analysis of dihydrochloride:
Compound 23: 2-chloro-11-(3-quinuclidinyl)amino-6,11-dihydrodibenzo[b,e]oxepin
[0146] m.p.: (dihydrochloride) 155°C (d.)
[0147] IR absorption spectrum (KBr tablet, cm
-1):
2940, 1485, 1260, 1115, 1005, 820
[0148] NMR spectrum (CDCl
3, δ value, ppm):
0.78-3.38(m, 13H), 4.54(s, 1H), 4.80(d, 1H), 6.28 & 6.38-(twin d, 1H), 6.62-7.55 (m,
7H),
[0149] Elemental analysis of dihydrochloride:
Compound 24: 2-methoxy-11-(3-quinuclidinyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0150] m.p.: (dihydrochloride) 185°C (d.)
[0151] IR absorption spectrum (KBr tablet, cm
-1) :
2930, 1495, 1260, 1205, 1040, 815
[0152] NMR spectrum (CDCl
3, δ value, ppm):
0.81 - 3.24 (m, 13 H), 3. 68 (s, 3H), 4. 48 (s, 1H), 4.79(d, 1H), 5.85 & 5.93 (twin
d, 1H), 6.43-7.41 (m, 7H)
[0153] Elemental analysis of dihydrochloride:
Compound 25: 2-methyl-11-{2-(1-piperazinyl)ethyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0154] m.p.: (t=ihydrochlcride) 143°C (d.)
[0155] IR absorption spectrum (NaCl cell, cm
-1):
2940, 1500, 1225, 1125, 1050, 820
[0156] NMR spectrum (CDCl
3, δ value, ppm):
2.23(s, 3H), 1.52-3.05(m, 14H), 4.45(s, 1H), 4.80(d, 1H), 6.08(d, 1H), 6.45-7.38 (m,
7H)
[0157] Elemental analysis of trihydrochloride: .
Compound 26: 2-ethyl-11-{2-(1-piperazinyl)ethyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0158] m.p.: (trihydrochloride) 170°C (d.)
[0159] IR absorption spectrum (KaCl cell, cm
-1):
2940, 1500, 1260, 1125, 1015, 825
[0160] NMR spectrum (CDCl
3, δ value, ppm)
1.18(t, 3H), 2.03-2.39 (m, 16H), 4.48(s, 1H), 4.82(d, 1H), 6.10(d, 1H), 6.59-7.46(m,
7H)
[0161] Elemental analysis of trihydrochloride:
Compound 27: 2-methyl-11-(1-ethyl-3-piperidyl)amino-6.11-dihydrodibenz[b,e]oxepin
[0162] m.p.: (dihydrochloride) 202°C (d.)
[0163] IR absorption spectrum (NaCl cell, cm
-1) :
2930, 1500, 1265, 1230, 1015, 820
[0164] NMR spectrum (CDCl
3, δ value, ppm):
2.21(s, 3H), 0.50-3.04(m, 14H), 4.64(s, 1H), 4.76(d, 1H), 6.24 & 6.29 (twin d. 1H),
6.50-7.57 (m, 7H)
[0165] Elemental analysis of dihydrochloride:
Compound 28: 2-methyl-11-{1-ethyl-2-pyrrolidinyl)methyl}- amino-6,11-dihydrodibenz[b,e]oxepin
[0166] m.p.: (dihydrochloride) 170°C (d.)
[0167] IR absorption spectrum (dihydrochloride, KBr tablet, cm
-1): 2650, 1630, 1435, 1215, 1030, 840
[0168] NMR spectrum (CDCl
3, δ value, ppm):
1.02(t, 3H), 2.23(s, 3H), 1.30-3.35(m, 12H), 4.49(s, 1H), 4.78(d, 1H), 6.31(d, 1H),
6.62-7.42 (m, 7H)
[0169] Elemental analysis of dihydrochloride:
Compound 29: 2-methyl-11-(4-methyl-1-piperazinyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0170] m.p.: (trihydrochloride being too hygroscopic to measure)
[0171] IR absorption spectrum (NaCl cell, cm
-1):
253C, 1500, 1260, 1125, 1015, 820
[0172] NMR spectrum (CDCl
3 , δ value, ppm) :
2.21(s, 3H)., 2.25(s, 3H), 2.95(s, 1H), 2.06-3.36 (m, 8H), 4.71(s, 1H), 4.75(d, 1H),
6.21(d, 1H), 6.53-7.46 (m, 7H)
[0173] Elemental analysis of trihydrochloride:
Compound 30: 2-fluoro-11-{(1,4-benzodioxane-2-)methyl}- amino-6,11-dihydrodibenz[b,e]oxepin
[0174] m.p.: (hydrochloride) 199 - 202°C
[0175] IR absorption spectrum (hydrochloride, KBr tablet, cm
-1): 1595, 1495, 1265, 1205, 1020, 750
[0176] NMR spectrum (hydrochloride, d
6-DMSO, δ value, ppm):
3.00-4.50(m, 7H), 4.98(d, 1H), 5:63(s, 1H), 5.77(d, 1H), 6.80 -7.70(m, 11H)
[0177] Elemental analysis of hydrochloride:
Compound 31: 2-fluoro-11-(bis-(4-fluorophenyl)methyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0178] m.p.: (hydrochloride) 105-108°C
[0179] IR absorption spectrum (NaCl cell, cm
-1):
3030, 1610, 1500, 1230, 830, 735
[0180] NMR spectrum (CCl
4, δ value ppm):
2.61 (s, 1H), 4.29(s, 1H), 4.55(s, 1H), 4.83(d, 1H), 5.81(d, 1H) , 6.50-7.50 (m, 15H)
[0181] Elemental analysis of hydrochloride:
Compound 32: 2-fluoro-11-{{1-methyl-3-phenyl)propyl}amino-6,11-dihydrodibenz [b, e]
oxepin
[0182] m.p.: (hydrochloride) 183-186°C
[0183] IR absorption spectrum (hydrochloride, KBr tablet, cm
-1): 1490, 1430, 1200, 1015, 830, 750
[0184] NMR spectrum (CCl
4, 6 value, ppm):
1.03 & 0.93 (twin d, 3H), 1.30-2.80(m, 6H), 4.55 (s, 1H), 4.71 (d, 1H), 6.18 & 6.35
(twin d, 1H), 6.60-7.30 (m, 12H)
[0185] Elemental analysis of hydrochloride:
Compound 33: 2-fluoro-11-{2-(diphenylmethyloxy)ethyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0186] m.p.: (hydrochloride) 184-187°C
[0187] IR absorption spectrum (hydrochloride, KBr tablet, cm
-1):
3020, 1495, 1205, 1
095, 1020, 7
55
[0188] NMR spectrum (
CC1
4 + d
6-DMSO, δ value, ppm):
2.29(s, 1H), 2.74(t, 2H), 3.52(t, 2H), 4.69(s, 1H), 4.75(d, 1H), 5.29(s, 1H), 6.10(d,
1H), 6.70-7.50 (m, 17H)
[0189] Elemental analysis of hydrochloride:
Compound 34: 2-fluoro-11-{2-(dibenzylamino)ethyl)amino-6,11-dihydrodibenz[b,e]oxenin
[0190] m.p.: (dihydrochloride) 196-198°C
[0191] IR absorption spectrum (dihydrochloride, KBr tablet, cm
-1): 2930, 1495, 1430, 1205, 1020, 755
[0192] NMR spectrum (CCl
4, δ value, ppm):
200 (s, 1H), 2.45(s, 4H), 3.42(s, 4H), 4.21(s, 1H), 4.61(d, 1H), 6.09(d, 1H), 6.60-7.40
(m, 17H)
[0193] Elemental analysis of dihydrochloride:
Compound 35: 2-ethyl-11-(2-piperidinoethyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0195] IR absorption spectrum (KBr tablet, cm
-1):
2930, 1500, 1260, 1125, 101.5, 825
[0196] NMR spectrum (CDCl
3, δ value, ppm):
1.18(t, 3H), 1.17 - 1.83(m, 6H), 2.10 - 2.90 (m, 11H),
4.50(s, 1H), 4.79(d, 1H), 6.15(d, 1H), 6.63 - 7.43(m, 7H)
[0197] Elemental analysis:
Compound 36 2-methyl-11-[2-(2-pyridyl)ethyl]amino-6,11- dihydrb.dibenz[b,e]oxepin
[0198] m.p.: (dihydrochloride) 184°C (d.)
[0199] IR absorption spectrum (NaCl cell, cm
-1) :
2930, 1595, 1500, 1230, 1010, 820
[0200] NMR spectrum (CDCl
3, δ value, ppm):
2.13(s, 1H), 2.21(s, 3H), 2.90(s, 4H), 4.53 (s, 1H),
4.70(d, 1H), 6.16(d, 1H), 6.60 - 7.70(m, 10H),
8.30 - 8.60 (m, 1H)
[0201] Elemental analysis of dihydrochloride:
Example 37
[0202] Preparation of compound 37: 2-nathyl-11-[4-(2-hydroxyethyl)-1-piperazinyl]-6,11-dihydrodibenz[b,e]-oxepin
[0203] In this example, 3.7 g of crude crystals of 2-methyl-11-chloro-6,11-dihydrodibenz[b,e]oxepin
obtained from 3.6 g of 2-methyl-6,11-dihydrodibenz[b,e]oxepinone-11 in the same amnner
as in Example 1 are dissolved in 6
0 ml of toluene and the solution is dropwise added to a solution of 9.8 g of l-(2-hydroxyethyl)
piperazine in 20 ml of toluene, followed by heating for 2 hours at 80°C. After completion
of the reaction, 30 ml of water is added thereto, and the pH of the solution is adjusted
to 2.0 with concentrated hydrochloric acid. Then, a toluene layer is discarded, and
20 ml of ethyl ether is added to an aqueous layer, followed by readjusting the pH
of the solution to 10.5 with a 10 N sodium hydroxide aqueous solution. The aqueous
layer is discarded, and the ethyl ether layer is dehydrated and concentrated under
reduced pressure. The residue is purified through silica gel chromatography. Concentration
of the main fractions gives 4.0 g of 2-methyl-ll-[4-(2-hydroxyethyl)-l-piperazinyl]-6,11-dihydrodibenz[b,e]oxepin
[compound 37] in an oily free base in a yield of 79%.
[0204] m.p. : (fumarate) 172 - 175°C
[0205] IR absorption spectrum (NaCl cell, cm ):
2950,.1500, 1235, 1120, 1010, 760
[0206] NMR spectrum (CDCl
3, 6 value, ppm):
2.21(s, 3H), 2.56(s, 8H), 2.06- 2.73(m, 2H), 3.58 (t, 2H), 3.83(s, 1H), 3.86(s, 1H),
4.65(d, 1H), 6.53-7.50 (m, 8H)
[0207] Elemental analysis of fumarate:
Examples 38 to 47
[0208] Compounds 38 to 47 are obtained in a similar manner to that in Example 37 except
that Compound II shown in Table 3 and amine are used instead of 2-methyl-6,11-dihydrodibenz
[b,e]oxepinone-11 (Compound II) and 1-(2-hydroxyethyl)-piperazine in Example 37.
Compound 38: 2-ethyl-11[4-(2-hydroxyethyl)-1-piperazinyl]-6,11-dihydrodibenz[b,e]oxepin
[0209] m.p.: (fumarate) 179°C (d.)
[0210] IR absorption spectrum (NaCl cell, cm
-1):
2955, 1500, 1225, 1140, 1005, 755
[0211] NMR spectrum (fumarate, d
6-DMSO, δ value, ppm):
1.11 (t, 3H), 2.14-2.84 (m, 12H), 3.52(t, 2H), 3.98(s, 1H), 4.70(d, 1H), 6.27-7.50 (m, 10H), 8.62 (broad s, 3H)
[0212] Elemental analysis of fumarate:
Compound 39: 2-fluoro-11-{4-(2-hydroxyethyl)-1-piperazinyl)}-6,11-dihydrodibenz[b,e]oxepin
[0213] m.p.: (dihydrochloride) 140°C (d.)
[0214] IR absorption spectrum (NaCl cell, cm ):
2810, 1495, 1255, 1140, 1000, 760
[0215] NMR spectrum (CDC1
3, 6 value, ppm): 2.40(s, 8H), 2.07-2.63(m, 2H), 2.83(s, 1H), 3.57(t, 2H), 3.82(s,
1H), 4.64 (d, 1H), 6.43-7.43 (m, 8H)
[0216] Elemental analysis of dihydrochloride:
Compound 40: 2-chloro-11-{4-(2-hydroxyethyl)-1-piperazinyl}-6,11-dihydrodibenz[b,e]oxepin
[0218] IR absorption spectrum (KBr tablet,
cm
-1):
2810, 1485, 1255, 1140, 1000, 815
[0219] NMR spectrum (CDC1
3, δ value, ppm): 2.42(s, 8H), 2.71(s, 1H), 2.16-2.93 (m, 2H), 3.58(t, 2H), 3.80 (s,
1H), 4.66(d, 1H), 6.56-7.39(m, 8H)
[0220] Elemental analysis:
Compound 41: 4-methyl-11-{4-(2-hydroxyethyl)-1-piperazinyl)-6,11-dihydrodibenz[b,e]oxepin
[0221] m.p.: (dihydrochloride) 161 - 164°C
[0222] IR absorption spectrum (NaCl cell, cm
-1):
2940, 1465, 1310, 1140, 1085, 1005
[0223] NMR spectrum (CDCl
3, δ value, ppm): 2.14(s, 3H), 2.40(s, 8H), 1.94-2.74(m, 3H), 3.55(t, 2H), 3.87(s,
1H), 4.75(d, 1H), 6.44-7.41 (m, 8H)
[0224] Elemental analysis of dihydrochloride:
Compound 42: 4-phenyl-11-{4-(2-hydroxyethyl)-1-piperazinyl)-6,11-dihydrodibenz[b,e]oxepin
[0225] m.p.: (dihydrochloride being too hygroscopic to measure)
[0226] IR absorption spectrum (dihydrochloride, KBr tablet, cm
-1) : 3020, 1635, 1435, 1210, 1020, 765
[0227] NMR.spectrum (CDCl
3, δ value, ppm):
2.40 (s, 8H), 1.94-2.74 (m, 3H), 3.56 (t, 2H), 3.92(s, 1H), 4.64(d, 1H), 6.43-7.62
(m, 13H)
[0228] Elemental analysis of dihydrochloride:
Compound 43: 2-fluoro-11-[4-{bis-(4-fluorophenyl)}methyl-1-piperazinyl]-6,11-dihydrodibenz[b,e]oxepin
[0230] IR absorption spectrum (KBr tablet, cm
-1):
2810, 1605, 1495, 1220, 1005, 820
[0231] NMR spectrum (d
6-acetone, δ value, ppm): 2.35(s, 8H), 3.98(s, 1H), 4.30(s, 1H), 4.68(d, 1H), 6.70-7.70
(m, 16H)
[0232] Elemental analysis:
Compound 44: 2-methyl-11-{4-(2-aminoethyl)-1-piperazinyl}-6,11-dihydrodibenz[b,e]oxepin
[0233] m.p.: (trihydrochloride) 146°C (d.)
[0234] IR absorption spectrum (KBr tablet, cm
-1) 2810, 1495, 1225, 1125, 1005, 815
[0235] NMR spectrum (CDC1
2, δ value, ppm):
2.20(s, 3H), 2.34(s, 8H), 1.65-2.92(m, 6H), 3.80(s, 1H), 4.63(d, 1H), 6.42-7.45(m,
8H)
[0236] Elemental analysis of trihydrochloride:
Compound 45: 2-ethyl-11-{4-(2-aminoethyl)-1-piperazinyl}-6,11-dihydrodihenz[b,e]oxepin
[0237] m.p.: (trihydrochloride) 130 - 133°C
[0238] IR absorption spectrum (NaCl cell, cm
-1):
2960, 1495, 1225, 1125, 1005, 825
[0239] NMR spectrum (CDCl
3, δ value, ppm): 1.18(t, 3H), 2.30(s, 2H), 2.37(s, 8H), 1.74-2.77(m, 6H), 3.85(s,
1H), 4.64(d, 1H), 6.51-7.51 (m, 8H)
[0240] Elemental analysis of trihydrochloride:
Compound 46: 2-fluoro-11-{4-(2-aminoethyl)-1-piperazinyl}-6,11-dihydrodibenz[b,e]oxepin
[0241] m.p.: (trihydrochloride) 134 - 137°C
[0242] IR absorption spectrum (trihydrochloride, KBr tablet, cm
-1):
1620,
1500, 144
0, 121
0, 1020, 760
[0243] NMR spectrum (CDC13, δ value, ppm):
1.70-3.20(m, 14H), 3.77(s, 1H), 4.62(d, 1H), 6.40-7.50 (m, 8H)
[0244] Elemental analysis of trihydrochloride:
Compound 47: 4-phenyl-11-(4-methyl-1-piperazinyl)-6,11-dihydrodibenz[b,e]oxepin
[0245] m.p. : (dihydrochloride) 132-135°C
[0246] IR absorption spectrum (NaCl cell, cm ):
2800, 1430, 1225, 1000, 850, 760
[0247] NMR spectrum (CDCl
3, δ value, ppm):
2.21(s, 3H), 2.39(s, 8H), 3.97(s, 1H), 4.64(d, 1H), 6.47 - 7.57 (m, 13H)
[0248] Elemental analysis of dihydrochloride:
Compound 48: 2-cyclohexyl-11-{2-(diethylamino)ethyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0249] m.p. : (dihydrochloride) 128-130°C
[0250] IR absorption spectrum (NaCl cell, cm ):
2930, 1500, 1455, 1260, 1230, 1020
[0251] NMR spectrum (CDC1
3, δ value, ppm):
0.93 (t, 6H), 0.63-2.07 (m, 10H), 2.07-2.80 (m, 10H), 4.50(s, 1H), 4.77(d, 1H), 6.13(d,
1H), 6.63-7.36 (m, 7H)
[0252] Elemental analysis of dihydrochloride:
Compound 49: 2-fluoro-11-{3-(dimethylamino)propyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0253] m.p.: (dihydrochloride) 199°C (d.)
[0254] IR absorption spectrum (NaCl cell, cm
-1) :
2940, 1495, 1260, 1225, 1195, 760
[0255] NMR spectrum (CDCl
3, δ value, ppm):
1.32-1.90(m, 2H), 2.13(s, 6H), 1.93-2.83(m, 5H), 4.50 (s, 1H), 4.85 (d, 1H), 6.06
(d, 1H), 6.56-7.49 (m, 7H)
[0256] Elemental analysis of dihydrochloride:
Compound 50: 2-chloro-11-(3-(dimethylamino)propyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0257] m.p.: (dihydrochloride) 200 °C (d.)
[0258] IR absorption spectrum (NaCl cell, cm
-1) 2940, 2830, 1485, 1255, 1230, 1010
[0259] NMR spectrum (CDCl
3, δ value, ppm):
1.36-1.86(m, 2H), 2.13 (s, 6H), 1.86-2.83 (m, 5H), 4.50 (s, 1H), 4.80 (d, 1H), 6.29 (d, 1H), 6.60-7.34 (m, 7H)
[0260] Elemental analysis of dihydrochloride:
Compound 51: 2-(1-methyl)propyl-11-(3-quinuclidinyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0261] m.p. : (dihydrochloride) 1
40 - 142°C
[0262] IR absorption spectrum (NaCl cell, cm
-1) 2950, 1500, 1455, 1200, 1230, 755
[0263] NMR δ value, ppm) : NMR spectrum (CDCl
3, δ value ppm) :
0.81 (t, 3H), 1.20(d, 3H), 0.50-3.30 (m, 16H), 4.56 (s, 1H), 4.78 & 4.81 (twin d,
1H), 6.17 & 6.30 (twin d, 1H), 6.60-7.46 (m, 7H)
[0264] Elemental analysis of dihydrochloride:
Compound 52.: 2-(1,1-dimethyl)ethyl-11-(3-quinuclidinyl)-amino-6,11-dihydrodibenz[b,e]oxepin
[0265] m.p.: (dihydrochloride) 145 - 149°C
[0266] IR absorption spectrum (NaCl cell, cm
-1) 2950, 1500, 1255, 1230, 1130, 1015
[0267] NMR spectrum (CDCl
3, δ value, ppm):
1.29(s, 9H), 0.71-3.21(m, 13H), 4.58 (s, 1H), 4.77 & 4.80(twin d, 1H), 6.19 & 6.32
(twin d, 1H), 6.64-7.47 (m, 7H)
[0268] Elemental analysis of dihydrochloride:
Compound 53: 2-(1,1-dimethyl)propyl-11-(3-quinuclidinyl)-amino-6,11-dihydrodibenz[b,e]oxepin
[0269] m.p.: (dihydrochloride) 141 - 144°C
[0270] IR absorption spectrum (NaCl cell, cm
-1) 2930, 2860, 1500, 1260, 1230, 730
[0271] NMR spectrum (CDCl
3, δ value, ppm) :
0.68 (t, 3H), 1.25(s, 6H), 0.92 - 3.11 (m, 15H), 4.58 (s, 1H), 4.75 & 4.82 (twin d,
1H), 6.19 & 6.31 (twin d, 1H), 6.59-7.46 (m, 7H)
[0272] Elemental analysis of dihydrochloride;
Compound 54 : 2-cyclohexyl-11-(3-quinuclidinyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0273] m.p. : (dihydrochloride) 140 - 143°C
[0274] IR absorption spectrum (KBr tablet, cm
-1) :
2920, 2850, 1500, 1455, 1230, 760
[0275] NMR spectrum (CDCl
3, 6 value, ppm) :
0.82-3.10 (m, 24H), 4.55(s, 1H), 4.81 (d, 1H), 6.16 & 6.30 (twin d, 1H), 6.62 - 7.35
(m, 7H)
[0276] Elemental analysis of dihydrochloride:
Compound 55: 2-phenyl-11-(3-guinuclidinyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0277] m.p.: (dihydrochloride) 148 - 150°C
[0278] IR absorption spectrum (NaCl cell, cm
-1) :
2940, 2870, 1485, 1250, 1230, 760
[0279] NMR spectrum (CDCl
3, δ value, ppm):
. 0.86-3.23 (m, 13H), 4.69(s, 1H), 4.86 (d, 1H), 6.41 & 6.51(twin d, 1H), 6.83-7.81 (m, 12H),
[0280] Elemental analysis of dihydrochloride:
Compound 56: 4-methyl-11-(3-quinuclidinyl)amino-6,11-dihydrodibenz[b,e]oxepin.
[0281] m.p. : (dihydrochloride) 150 - 153°C
[0282] NMR spectrum (CDCl
3, δ value, ppm):
2.22(s, 3H), 0.82-3.16(m, 13H), 4.55(s, 1H), 4.87 (d, 1H), 5.98 & 6.13 (twin d, 1H),
6.45-7.32 (m, 7H)
[0283] Elemental analysis of dihvdrochloride:
Compound 57: 4-phenyl-11-(3-quinuclidinyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0284] m.p.: (dihydrochloride) 153 - 155°C
[0285] IR absorption spectrum (KBr tablet, cm
-1) :
2930, 1470, 1435, 1220, 1010, 760
[0286] NMR spectrum (CDCl
3, δ value, ppm) 0.90-3.47 (m, 13H), 4.61(s, 1
H), 4.74 (d, 1
H), 5.67 & 5.82 (twin d, 1H), 6.70-7.93 (m, 12H)
[0287] Elemental analysis of dihydrochloride:
Compound 58: 2-methyl-11-{2-(1-pyrrolidinyl) ethyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0288] m.p. : (dihydrochloride) 154 - 157°C
[0289] IR absorption spectrum (NaCl cell, cm
-1):
2960, 2790, 1500, 1260, 1230, 1120
[0290] NMR spectrum (CDCl
3, δ value, ppm) :
1.33-1.93 (m, 4H), 2.20(s, 3H), 2.00-2.90 (m, 9H), 4.47 (s, 1H), 4.75(d, 1H), 6.20
(d, 1H), 6.63-7.39 (m, 7H)
[0291] Elemental analysis of dihydrochloride:
Compound 59: 2-methyl-11-(2-morpholinoethyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0293] IR absorption spectrum (KBr tablet, cm
-1) :
2810, 1500, 1260, 1230, 1115, 760
[0294] NMR spectrum (CDCl
3, 6 value, ppm):
2.24 (s, 3H), 2.06-2.83 (m, 9H), 3.60 (t, 4H), 4.46 (s, 1H), 4.81 (d, 1H), 6.07 (d.
1H), 6.62-7.36 (m, 7H)
[0295] Elemental analysis:
Compound 60: 2-fluoro-11-{2-(3,4-dimethoxyphenyl)ethyl}- amino-6,11-dihydrodibenz[b,e]oxepin
[0296] m.p. : (dihydrochloride) 222 °C (d.)
[0297] IR absorption spectrum (NaCl cell, cm
-1) :
2940, 1500, 1260, 1240, 1145, 1030
[0298] NMR spectrum (CDCl
3, δ value, ppm):
1.95(s, 1H), 2.52 - 2.96 (m, 4H), 3.75(s, 3H), 3.77(s, 3H), 4.49(s, 1H), 4.78 (d ,
1H), 5.95(d, 1H), 6.42 - 7.39(m, 10H)
[0299] Elemental analysis of dihydrochloride:
Compound 61: 2-ethyl-11-(5-quinolyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0301] IR absorption spectrum (KBr tablet, cm
-1):
2960, 1615, 1580, 1480, 1415, 790
[0302] NMR spectrum (CDCl
3, δ value, ppm):
1.13 (t, 3H), 2.13 - 2.90 (m, 2H), 5.01(d, 1H), 5.54(s, 1H), 5.83(d, 1H), 4.63 - 6.08
(broad, 1H), 6.46 - 7.80 (m, 11H), 7.89 - 8.32 (m, 1H), 8.50 - 8.93 (m, 1H)
[0303] Elemental analysis:
Compound 62: 2-methyl-11-(5-indolyl)amino-6,11-dihydrodibenz[b,e]oxepin
[0304] m.p.: (dihydrochloride) 184 °C (d.)
[0305] IR absorption spectrum (NaCl cell, cm
-1):
1500, 1465, 1250, 1225, 820, 755
[0306] NMR spectrum (CDCl
3 δ value, ppm):
2.16(s, 3H), 4.17 (broad, 1H), 4.95 (d, 1H), 5.30(s, 1H), 5.82 (d, 1H), 6.10 - 7.57
(m, 12H), 7.77(broad, 1H)
[0307] Elemental analysis of dihydrochloride:
Compound 63: 2-ethyl-11-{4-(2,2,6,6-tetramethyl)-piperidinyl}amino-6,11-dihydrodibenz[b,e]oxepin
[0308] m.p.: (dihydrochloride) 198°C (d.)
[0309] IR absorption spectrum (NaCl cell, cm
-1):
2960, 1500, 1260, 1230, 1015, 755
[0310] NMR spectrum (CDCl
3, δ value, ppm):
1.03(s, 12H), 1.17(t, 3H), 0.36 - 2.16 (m, 5H), 2.22 - 3.12 (m, 4H), 4.74(s, 1H),
4.77(d, 1H), 6.16(d, 1H), 6.66 - 7.45 (m, 7H)
[0311] Elemental analysis of dihydrochloride:
Compound 64: 2-methyl-11-[N-{2-(dimethylamino)ethyl}-N-ethyl]amino-6,11-dihydrodibenz[b,e]oxepin
[0312] m.p.: (dihydrochloride being too hygroscopic to measure)
[0313] IR absorption spectrum (NaCl cell, cm
-1):
2970, 1500, 1260, 1225, 1015, 755
[0314] NMR spectrum (CDCl
3, δ value, ppm):
0.90(t, 3H), 1.99 (s, 6H), 2.16(s, 3H), 1.80 - 2.86 (m, 6H), 4.23(s, 1H), 4.61(d,
1H), 6.49 - 7.29 (m, 8H)
[0315] Elemental analysis of dihydrochloride:
Compound 65: 2-methyl-11-(1',3'-dioxoran-2'-spiro- piperidino)-6,11-dihydrodibenz[b,e]cxepin
[0317] IR absorption spectrum (KBr tablet, cm
-1):
2950, 1500, 1260, 1225, 1145, 1070
[0318] NMR spectrum (CDCl
3, δ value, ppm):
1.63 (t, 4H), 2.20(s, 3H), 2.48 (t, 4H), 3.86(s, 5H), 4.65(d, 1H), 6.54 - 7.37 (m,
8H)
[0319] Elemental analysis:
Compound 66: 2-ethyl-11-(4-methyl-1-piperazinyl)-6,11-dihydrodibenz[b,e]oxepin
[0321] IR absorption spectrum (KBr tablet, cm
-1):
2800, 1500, 1290, 1225, 1155, 1005
[0322] NMR spectrum (CDCl
3, δ value, ppm):
1.16(t, 3H), 1.85 - 2.85 (m, 13H), 3.82 (s, 1H), 4.64(d, 1H), 6.52 - 7.62 (m, 8H)
[0323] Elemental analysis:
Compound 67: 2-methyl-11-(4-methyl-1-piperazinyl)-6,11-dihydrodibenz[b,e]oxepin
[0324] m.p.: (fumarate) 168 - 170°C
[0325] IR absorption spectrum (KBr tablet, cm
-1) :
2790, 1500, 1230, 1155, 1010, 760
[0326] NMR spectrum (fumarate, d
6-DMSO, δ value, ppm):
1.88 - 3.02 (m, 14H), 3.98(s, 1H), 4.72 (d, 1H), 6.25 - 8.08 (m, 12H)
[0327] Elemental analysis of fumarate:
Compound 68 : 2-methoxy-11-(4-methyl-1-piperazinyl)-6,11-dihydrodibenz[b,e]oxepin
[0328] m.p.: (fumarate) 167 - 170°C
[0329] IR absorption spectrum (NaCl cell, cm
-1):
2930, 2790, 1495, 1225, 1220, 1145
[0330] NMR spectrum (CDCl
3, δ value, ppm):
2.13(s, 3H), 2.72(s, SH), 3.70(s, 3H), 4.05(s, 1H), 4.67 (d, 1H), 6.20 - 7.40 (m,
8H)
[0331] Elemental analysis of fumarate:
Compound G9: 2-fluoro-11-(4-methyl-1-piperazinyl)-6,11-dihydrodibenz[b,e]oxepin
[0333] IR absorption spectrum (KBr tablet, cm
-1):
2790, 1495, 1260, 1140, 1005, 820
[0334] NMR spectrum (CDCl
3, δ value, ppm):
2.22(s, 3H), 2.37(s, 8H), 3.81(s, 1H), 4.67(d, 1H),
6.57 - 7.51(m, 8H)
[0335] Elemental analysis:
Compound 70: 2-chloro-11-(4-methyl-1-piperazinyl)-6,11-dihydrodibenz[b,e]oxepin
[0336] m.p.: (dihydrochloride) 258°C (d.)
[0337] IR absorption spectrum (dihydrochloride, KBr tablet, cm
-1)
2600, 1630, 1485, 1255, 1000, 830
[0338] NMR spectrum (CDCl
3, δ value, ppm):
2.21(s, 3H), 2.35(s, 8H), 3.80 (s, 1H), 4.66(d, 1H),
6.51 - 7.67(m, 8H)
[0339] Elemental analysis of dihydrochloride:
Example 71: Preparation of tablet
[0340] A tablet comprising the following components is prepared in a conventional manner.
Component
[0341]
Example 72: Preparation of powder
[0342] A powder comprising the following components is prepared in a conventional manner.
[0343] Component
Example 73: Preparation of syrup
[0344] A syrup comprising the following components is prepared in a conventional manner.
[0345] Component
[0346] Water is added to the above components dissolving the above components, until the
total volume is 100 cc.